In this project, we will investigate the role of Ire1, a critical regulator of the unfolded protein response (UPR), in modulating the tumor response to hypoxia and radiation. We have completed a high throughput small molecule screen of >120,000 compounds and identified several classes of lre1 inhibitors. We and other investigators have shown that lre1 endonuclease activity is specific for splicing XBP-1 into its active form and that XBP-1 activation is responsible for mediating survival under hypoxia and ER stress. We will develop small molecule inhibitors for Irel's specific endonuclease activity as a therapeutic strategy for breast and pancreatic cancer. We have also developed an XBP-1-luciferase transgenic reporter mouse in which we can follow Irel activity in tumors in order to optimize the dosing schedules of our Irel inhibitors. These studies will be conducted in an MMTV-Tag breast tumor model as well as a pancreatic cancer orthotopic tumor model as these tumor models reflect important aspects of the tumor microenvironment that more closely resembles human cancer. In addition, because of our data showing that ER stress within the tumor microenvironment may modulate radiation response, we will determine the role of Irel in the radiation response of aerobic and hypoxic cells to radiation. These studies will be performed in tumor cell lines in which Irel has been genetically deleted inhibited as well as in orthotopic pancreas tumors in which Irel is pharmacologically manipulated. These data will help to define the role of Irel in the response of tumors to hypoxia and radiation. This knowledge will further the development of molecular strategies to target Irel for cancer therapy.